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Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine. All content is Derek’s own, and he does not in any way speak for his employer.

Alzheimer's Disease

Eli Lilly’s Brave Alzheimer’s Talk

I’m a bit baffled by Eli Lilly’s strategy on Alzheimer’s. Not the scientific side of it – they’re going strongly after the amyloid hypothesis, with secretase inhibitors and antibody therapies, and if I were committed to the amyloid hypothesis, that’s probably what I’d be doing, too. It is, after all, the strongest idea out there for the underlying mechanism of the disease. (But is it strong enough? Whether or not amyloid is the way to go is the multibillion dollar question that can really only be answered by spending the big money in Phase III trials against it, unfortunately).
No, what puzzles me is the company’s publicity effort. As detailed here and here, the company recently made too much (it seemed to me and many others) of the results for solanezumab, their leading antibody therapy. Less hopeful eyes could look at the numbers and conclude that it did not work, but Lilly kept on insisting otherwise.
And now we have things like this:

“We are on the cusp here of writing medical history again as a company, this time in Alzheimer’s disease,” Jan Lundberg, Lilly’s research chief, said in an interview.
Just as the Indianapolis-based company made history in the 1920s by producing the first insulin when type 1 diabetes was a virtual death sentence, Lundberg said he is optimistic that the drugs Lilly is currently testing could significantly slow the ultimately fatal memory-robbing disease.
“It is no longer a question of ‘if’ we will get a successful medicine for this devastating disease on the market, but when,” said Lundberg, 59.

Ohhh-kay. The problems here are numerous. For one thing, as Lundberg (an intelligent man) well knows, insulin-for-diabetes is a much straighter shot than anything we know of for Alzheimer’s. It was clear, when Lilly got their insulin business underway, that the most devastating symptoms of type I diabetes were caused by lack of insulin production in the body, and that providing that insulin was the obvious remedy. Even if it did nothing for the underlying cause of the disease (and it doesn’t), it was a huge step forward. As for Alzheimer’s, I understand that what Lundberg and Lilly are trying to get across here is the idea of a “successful medicine”, rather than a “cure”. Something that just slows Alzheimer’s down noticeably would indeed be a successful medicine.
But “when, not if”? With what Lilly has in the clinic? After raising hopes by insisting that the Phase III results for solanezumab were positive, the company now says that. . .well, no, it’s not going to the FDA for approval. It will, instead, conduct a third Phase III trial. This decision came after consulting with regulators in the the US and Europe, who no doubt told them to stop living in a fantasy world. So, sometime next year, Lilly will start enrolling for another multiyear shot at achieving some reproducible hint of efficacy. Given the way solanezumab has performed so far, that’s about the best that could be hoped for, that it works a bit in some people, sometimes, for a while, as far as can be told in a large statistical sample. Which sets up this situation, I fear.
And this is “on the cusp. . .of writing medical history”? Look, I would very much like for Lilly, for anyone, to write some medical history against Alzheimer’s. But saying it will not make it so.

ah hubris. it has worked so well in the past, why not give it a shot again.
@1, silly is putting it nicely. As an academic currently working on understanding AD, the A-beta hypothesis is being laughed out the window. JohnnyBoy has it right, the only history being written is an obituary

@Josh: Can you provide any references to back up the claim that it is being laughed out the window? I am also in AD and as far as I can tell, it is being given quite a lot of consideration as acting alongside of Tau related neurodegeneration. Seems like people are thinking it might be the two halves to the puzzle.

From the discouraging results of the first phase III clinical trials, one is left with two conclusions: either solanezumab did not hit the target (amyloid plaques) hard enough or amyloid plaques are not the appropriate target once the disease has progressed past a certain point. It is not that Alzheimer’s disease cannot be treated past a certain point rather it is that Alzheimer’s disease cannot be treated with drugs that inhibit or remove amyloid plaques past a certain point.
The pathway to Alzheimer’s disease can be found on the left side of BioCarta’s Phospholipase C signaling pathway. It is phospholipase C that increases the release of beta-secretase and increases the activity of the gamma-secretase which leads to the formation of amyloid plaques (phospholipase C also increases the release of acetylcholinesterase). However, it is this sequence that is critical for the progression of Alzheimer’s disease: phospholipase C, protein kinase C, MAPK (especially p38 but perhaps also JNK), induction of NF-kB and the activation of NADPH oxidase, peroxynitrites. As the disease progresses the activity of both forms of phospholipase C declne and so too does the deposition of amyloid plaques and the activity of acetylcholinesterases. And while amyloid plaques may contribute to the formation of peroxynitrites, this formation may be primarily driven by the peroxynitrite activation of protein kinase C. Much of the damage done by peroxynitrites to the brain in Alzheimer’s disease can be reversed (even neurons in the hippocampus can be regenerated) but only with peroxynitrite scavengers.
On other sites, a person who seems to have some inside knowledge suggests that the Merck compound is related to curcumin. Curcumin is a phospholipase C gamma inhibitor (and thus a b-secretase inhibitor) and is also a peroxynitrite scavenger. The Merck Millipore website shows interest by the company in peroxynitrite scavengers and an awareness that peroxynitrites contribute to many diseases (although Alzheimer’s disease is not listed as one of them). So maybe there is something behind Merck’s confidence this time. Given their past track record with Vioxx and Fosamax (a peroxynitrite producing drug),though, I would not count on them to get it right.

I just read the history of the two companies and you are correct. So maybe the U.S. Merck is not interested in peroxynitrite scavengers to treat Alzheimer’s disease and maybe its product is not related to curcumin.
The research regarding peroxynitrites as critical to the pathogenesis of Alzheimer’s disease and the use of peroxynitrite scavengers to treat the disease is quite substantial dating back to the mid-1990s.

So, I don’t work in this area, but from what I understand of the amyloid hypothesis: presumably, the amyloid that is in the plaques, beta-amyloid, comes from the abnormal breakdown of APP, which is part of the normal neuronal membrane. The deposition of this beta-amyloid then alter the surrounding neurons’ function and survival. Is this roughly correct ?
If so, this would be a local mechanism, occurring within the brain. So how would a circulating antibody, which doesn’t penetrate the blood brain barrier, be expected to act upon the amyloid ? And even if it did penetrate and bind to amyloid, how would this be expected to be beneficial ? Presumably the binding would cause precipitation, then some sort of immune reaction, either through complement activation, or through phagocytic cell capture, digestion and cytokine release. Either of these broad mechanisms would be expected to cause a significant local inflammatory reaction in the brain, which couldn’t possibly be beneficial. If anyone reading is actually involved in AD research, could you pass along the current thinking as to these issues ? I’m genuinely interested in the reasoning behind this therapeutic approach.

@johnnyboy,
The amyloid hypothesis has several arguments that support it.
The first is that several mutations in the APP gene predispose to altered production of amyloid as well as to early onset Alzheimer’s disease (which looks the same, pathologically, as the more common late-onset Alzheimer’s disease). Furthermore, all the mutations in APP that cause early onset Alzheimer’s disease are located either within or immediately adjacent to a ~40 amino acid region of the protein that goes on to become amyloid, but not in the rest of the 695 amino-acid protein.
The second is that mutations in another gene, presenilin, also predispose to early onset Alzheimer’s disease and modify the production of amyloid. Presenilin is in fact an essential component of the protease complex called gamma-secretase that is required for the production of amyloid from APP. Thus all the mutations in APP that cause early onset Alzheimer’s are located in the region known to interact with presenilin.
Finally, soluble species of amyloid are toxic to cultured mouse neurons (but only at high concentrations), however, oddly, they are not toxic to neurons within a mouse brain.
Contrary arguments include the fact that not all Alzheimer’s-causing mutation in presenilin modify the production of amyloid, and that soluble amyloid actually declines, rather than increases, with onset and progression of late-onset Alzheimer’s disease.
The debate rages on…. These clinical trials are therefore very interesting, and also risky…

Let’s face it, Lilly doesn’t need a great drug to make billions, it just needs something that will get FDA approval, then they can turn their marketing machine loose on all of the desperate patients out there.

As an amusing footnote, Lilly was also quoted in an October 2010 press report as saying that, starting in 2013, “its bulging pipeline will begin to produce two new drugs per year”. It added that it was preparing a “statistical analysis to prove that two new drugs a year is not only a prediction but a probability”.
Hyperbole and science do not mix well. Lilly should know better. These sorts of silly statements amuse everyone, convince no one, and bring discredit upon the executives that make them.

@ 11 – bank,
thanks for your detailed answer. However, what you present are arguments for amyloid being associated with the pathophysiology of Alzheimer’s. Even if these hold up, there is a significant gap between the propositions “amyloid is causally related to AD” and “giving an IV antibody against amyloid will help treat AD”. It’s the thinking behind the therapeutic approach that I don’t quite grasp. If AD is indeed causally linked to abnormal amyloid production, some small molecule that could penetrate the BBB and act on neurons to reduce production of this abnormal amyloid would make sense; an IV antibody does not.

@ 15 johnnyboy
You’re right. Bank missed your question entirely. The answer is that in the blood you have these antibodies and in the brain you have the antigens. How do the antigens get from the brain to the blood? The answer, of course, is “tunneling”. Otherwise, it ain’t gonna happen.

There is indeed no evidence that amyloid plaques are directly toxic to the brain. If you inhibit the production of amyloid plaques with BACE and y-secretase inhibitors, you do not stop the production of peroxynitrites, which are the true cause of damage to neurons, transport systems, receptors, and enzymes in the brain including those involved in the production and release of acetylcholine in the hippocampus–a compound critical for short-term memory.
More than a dozen articles can be cited in support of this contention, but I will just cite one:
Behav Brain Res. 2007 Jun 18;180(2):139-45. Epub 2007 Mar 12.
A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).
Alkam T, Nitta A, Mizoguchi H, Itoh A, Nabeshima T.
SourceDepartment of Neuropsychopharmacology & Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
Abstract
Peroxynitrite (ONOO(-))-mediated damage is regarded to be responsible for the cognitive dysfunction induced by amyloid beta protein (Abeta) in Alzheimer’s disease (AD). In the present study, we examined the protective effects of rosmarinic acid (RA), a natural scavenger of ONOO(-), on the memory impairment in a mouse model induced by acute i.c.v. injection of Abeta(25-35). Mice daily received i.p. several doses of RA after the injection of Abeta(25-35). RA prevented the memory impairments induced by Abeta(25-35) in the Y maze test and novel object recognition task. RA, at the effective lowest dose (0.25mg/kg), prevented Abeta(25-35)-induced nitration of proteins, an indirect indicator of ONOO(-) damage, in the hippocampus. At this dose, RA also prevented nitration of proteins and impairment of recognition memory induced by ONOO(-)-i.c.v.-injection. Co-injection of the non-memory-impairing dose of ONOO(-) with Abeta(25-35) blocked the protective effects of RA (0.25mg/kg). These results demonstrated that the memory protective effects of RA in the neurotoxicity of Abeta(25-35) is due to its scavenging of ONOO(-), and that daily consumption of RA may protect against memory impairments observed in AD.
Indeed the most concentrated methoxyphenols compounds have partially reversed Alzheimer’s disease in human beings. This includes eugenol in rosemary essential oil via aromatherapy and ferulic acid, coumaric acid, syrinigic acid, and vanillic acid in heat-processed ginseng. Slowing down the production of amyloid plaques or increasing their clearance, only slows down the production of peroxynitrites and thus only slows down the progression of the disease, and in the case of solanezumab only minutely.

@johnnyboy, 16
How the antibodies clear amyloid is of course curious, as one would not expect them to cross the blood-brain barrier. However, the experimental observation is that they do, both in mice and in human clinical trials (in the bapineuzumab trial, if I remember).
Mice don’t get amyloid-mediated neurodegeneration, so the hypothesis that amyloid causes AD cannot be tested in mice. This is why these trials are interesting, since they are a bona fide, if imperfect, test of the amyloid hypothesis.

I apologize for keep hammering away on these points, but if not little progress will be made against Alzheimer’s disease for decades. The amount of amyloid plaque removed by bapineuzumab was reported to be about 7 percent. I have not seen figures for solanezumab. The IVIG (intravenous immunoglobulin) antibody supposedly has a much higher rate of removing plaques. This could be the reason for its initially more positive results. Or IVIG may be reducing a blood factor such as eotaxin that may contribute to the formation of plaques. Or IVIG may suppress TNF-alpha expression (tumor necrosis factor)which would limit the production of peroxynitrites. This would also help limit the nitration and aggregation of plaques. So some other mechanism or mechanisms may be involved in the reduction of plaques other than or in addition to as an antibody for amyloid plaques.
All of these approaches are expensive, largely ineffective, and fraught with potentially very serious side effect. None of which is true for peroxynitrite scavengers.
How do I know (or think I know) that peroxynitrites are the proper target for Alzheimer’s disease. Because all the risk factors for Alzheimer’s disease increase peroxynitrite formation, all the factors that supposedly can delay the onset of Alzheimer’s disease (such as phenolic compounds and polyunsaturated fats) reduce the formation of peroxynitrites, all the symptoms of Alzheimer’s disease are directly, indirectly, or in conjunction with other factors the result of peroxynitrite formation, and every peroxynitrite scavenger ever tested has ameliorated Alzheimer’s disease in vitro, in animals, or in human beings. Developing synthetic products for natural compounds to treat diseases no longer seems to be en vogue, but if pharmaceutical companies really want to treat Alzheimer’s disease effectively go back and study the history.